Diabetes causes various metabolic abnormalities including a chronic hyperglycemia state as a main characteristic, which shows various symptoms based on mouth dryness, polydipsia, polyuria, decrease in body weight and the like, based on hyperglycemia. It is known that, when such hyperglycemia state is maintained for a long time, various complications such as retinopathy, nephropathy, neuropathy, cardiac infarction and cerebral infarction based on arteriosclerosis, and the like are developed.
Diabetes is roughly divided into four types of type I diabetes (IDDM; Insulin Dependent Diabetes Mellitus), wherein pancreatic beta cells are damaged or destroyed to cause absolute insulin deficiency, type II diabetes (NIDDM; Non-Insulin Dependent Diabetes Mellitus) wherein relative insulin deficiency is developed due to insulin resistance and lower insulin secretion, specific diabetes which secondarily results from genetic abnormalities, other diseases and the like, and gestational diabetes. Some of those diagnosed with type II diabetes at the time of the onset may gradually lose their ability to secrete insulin with the progression of the disease and result in type I diabetes.
Considering the saccharometabolism of living organisms, energy sources and materials to be the constituent components of living organisms are taken into the body intermittently; for example, the brain keeps on consuming glucose. Under such situation, the blood glucose level is maintained almost constantly, and what enables such control of the blood glucose level includes hormones involved in control of the blood glucose level, metabolism in organs, interaction of exchanging sugar and the like between organs. Of such hormones, particularly the action of insulin involved in the control of the blood glucose level is important, and its disorder, namely, insulin resistance and lower secretion of insulin are considered to be deeply involved in diabetes.
Insulin is secreted from pancreatic beta cells, binds with an insulin receptor present on the membrane surface of the skeletal muscle cell and adipocyte, which are its target cells, after which tyrosine residue in the intracellular domain is self-phosphorylated. Then, tyrosine residues such as insulin receptor substrate (IRS), APS (adapter protein containing PH and SH2 domain) and the like are phosphorylated and PI3 kinase -Akt pathway is activated, which causes translocation of glucose transporter to cell membrane, where glucose uptake occurs to lower the blood glucose level. On the other hand, tyrosine phosphatase that causes tyrosine dephosphorylation to negatively control intracellular signal transduction by insulin is also present, and suppresses activation thereof. In this way, while tyrosine phosphorylation plays a key role in the insulin action, considering that tyrosine phosphorylation depends on the activity balance between tyrosine kinase (phosphorylation enzyme) and tyrosine phosphatase (dephosphorylation enzyme), tyrosine phosphatase is presumed to have function to significantly control insulin signal transduction directly together with tyrosine kinase.
At present, tyrosine phosphatase forms a large gene family and more than 70 some kinds of isozyme have been reported. Of such isozymes, protein tyrosine phosphatase 1B (PTP1B) is considered to be a phosphatase specific to insulin signal transduction. Particularly, given the reports on increased gene expression of PTP1B by high glucose culture, and shift of intracellular localization thereof, which decreases insulin receptor and IRS-1 tyrosine phosphorylation and induces insulin resistance (J. Biol. Chem., 270: 7724–7730, 1995; J. Biochem. (Tokyo), 123: 813–820, 1998); and introduction of wild-type PTP1B prevents translocation of glucose transporter GLUT4, resulting in ineffectiveness in a phosphatase activity deficient mutant, and recently on enhanced insulin sensitivity of PTP1B knockout mouse to be obesity resistant to high-fat diet (Science, 283: 1544–1548, 1999), this enzyme is suggested to be one possible target of insulin resistance improvement. In fact, an insulin resistance improvement effect of vanadic acid long known as a tyrosine phosphatase inhibitor has been acknowledged in animal test and the like.
Accordingly, such tyrosine phosphatase, particularly a drug that suppresses and/or inhibits abnormal activation of PTP1B can be a new type of therapeutic agent for diabetes, which enhances insulin sensitivity, insulin resistance and/or glucose resistance, and restores normal insulin intracellular signal transduction. In addition, application to a therapeutic drug for various diseases such as obesity, neurodegenerative disease and the like is also expected.
Recently, various reports have been documented on compounds aiming at treatment of diseases such as diabetes and the like, by inhibiting protein tyrosine phosphatase.
For example, WO 00/17211 discloses a phosphonic acid derivative having a PTP1B inhibitory action. However, this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof.
JP-11-508919A (U.S. Pat. No. 5,770,620) discloses an arylacrylic acid derivative useful as a protein tyrosine phosphatase inhibitor. However, this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof.
WO 98/27092 (U.S. Pat. No. 6,080,772) discloses a thiazole compound having a protein tyrosine phosphatase inhibitory action. However, this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof.
WO 99/58522 discloses a naphtho[2,3-B]heteroal-4-yl derivative, WO 99/58511 discloses an oxa/thiazole-aryl-carboxylic acid derivative, WO 99/58521 and U.S. Pat. No. 6,110,962 disclose 11-aryl-benzo[B]naphtho[2,3-D]furan and 11-aryl-benzo[B]naphtho[2,3-D]thiophene derivatives, WO 99/58518 discloses a biphenyl-oxo-acetic acid derivative, WO 99/61419 discloses a 2,3,5-substituted biphenyl derivative, WO 99/58520 discloses a biphenyl-sulfonyl-aryl-carboxylic acid derivative, WO 99/61435 discloses benzothiophene, benzofuran and indole derivatives, U.S. Pat. No. 6,103,708 discloses furan, benzofuran and thiophene derivatives, U.S. Pat. No. 6,110,963 discloses an aryl-oxo-acetic acid derivative, U.S. Pat. No. 6,001,867 discloses a 1-aryl-dibenzothiophene derivative, U.S. Pat. No. 6,057,316 discloses a 4-aryl-1-oxa-9-thia-cyclopenta[B]fluorene derivative, U.S. Pat. No. 6,063,815 discloses a benzophenone derivative, as each having a protein tyrosine phosphatase inhibitory action. However, these publications do not disclose compounds having a structure as that of the compound of the present invention, not to mention a description suggestive thereof.
As compounds having a thiazole or oxazole structure, the following have been reported.
WO 00/45635 discloses a 2-substituted thiazole derivative. However, the compound of this publication has a carbamoyl group at the terminal of the substituent at the 2-position of the thiazole ring and this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof. In addition, the compound of this publication is useful as an antimicrobial agent or an analgesic, and the publication does not disclose its usefulness as a PTP1B inhibitor, not to mention a description suggestive thereof.
JP-2000-504039A describes a 2-anilino-4-phenylthiazole derivative. However, the compound of this publication has an anilino group substituted by a hydroxyl group or a carboxyl group at the 2-position of a thiazole ring, a phenyl group at the 4-position, and a substituent at the 2-position of the 4-position phenyl group, and this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof. In addition, the compound of this publication is useful as a CRF (corticotropin releasing factor) antagonist, and the publication does not disclose its usefulness as a PTP1B inhibitor, not to mention a description suggestive thereof.
JP-A-4-154773 describes a thiazole derivative represented by the formula
wherein R1 and R2 are the same or different and each is hydrogen atom, halogen atom, lower alkyl group, phenyl group, substituted phenyl group, pyridyl group or substituted pyridyl group, R3 is hydroxyl group, lower alkoxy group or —N(R5)(R6) wherein R5 and R6 are the same or different and each is hydrogen atom or lower alkyl group, R4 is hydrogen atom or lower alkyl group, and X is amino group, amide group, carbonyl group, alkylene group, oxygen atom or sulfur atom. However, this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof. In addition, the compound of this publication is useful as an antiinflammatory agent, and the publication does not disclose its usefulness as a PTP1B inhibitor, not to mention a description suggestive thereof.
WO 94/08982 describes a 4-phenylthiazole derivative. However, the compound of this publication has phenyl group at the 4-position of a thiazole ring, and a substituent such as halogen and the like at the 2-position of the 4-position phenyl group. This publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof. In addition, the compound of this publication is useful as a pest control agent, and the publication does not disclose its usefulness as a PTP1B inhibitor, not to mention a description suggestive thereof.
WO 02/39997 describes compounds represented by the formula
wherein R6 is hydroxyl group or protected prodrug moiety, R7 is hydrogen atom, carboxy group, arylaminocarbonyl group, aroyl group, aryl group, alkylaminocarbonyl group, aminocarbonyl group, alkenylaminocarboxy group, hydroxyl group, alkoxy group, ether, thiol, amino group-containing heterocyclic group or protected prodrug moiety, R8 is hydrogen atom or alkyl group that may be bonded with D to form a ring, R9 is lower alkyl group or hydrogen atom, Q is bond, oxygen atom, sulfur atom, CR3OH, CR3SH, CR3NR3aR3b, NR3, (CR3R3a)n, O(CR3R3b)n or (CR3R3a)nO(CR3bR3c)n wherein n is an integer of 0 or 1 to 3, R3, R3a, R3b and R3c are each independently hydrogen atom, optionally substituted straight chain, cyclic or branched chain C1-6 alkyl group, C2-6 alkenyl group, acyl group, arylalkyl group, aryloxycarbonyl group, arylaminocarbonyl group, arylalkylsulfonyl group or aryl group, G is a linking moiety, M is anchor moiety, J is bond, alkylene group, alkenylene group or alkynylene group, D is hydrogen atom, alkoxy group, amine, alkyl group, alkenyl group, alkynyl group, aryl group or heteroaryl group that may be bonded with G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is 0 or an integer of 1 to 3, andthe formula
wherein P4 is carboxy group, cleavable prodrug moiety, COOP4′, (CH2)1-4SP4′ or C(O)NP4′P4″, R7 is hydrogen atom, carboxy group, optionally substituted lower alkyl ester, lower alkenyl ester, ester added with secondary amine substituted by lower alkyl, arylaminocarbonyl group, aroyl group, aryl group, alkylaminocarbonyl group, aminocarbonyl group, COOR7′, CONR7′R7″, hydroxyl group, ether, thiol, amino group, (CH2)1-4SR7′, heterocyclic group or cleavable prodrug moiety, P4′, P4″, R7′ and R7″ are each independently hydrogen atom, C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group or optionally substituted aryl group, R8 is hydrogen atom, alkyl group or covalent bond with D, R9 is lower alkyl group or hydrogen atom, Q is bond, oxygen atom, sulfur atom, CR3OH, CR3SH, CR3NR3aR3b, NR3, (CR3R3a)n, O(CR3R3b)n or (CR3R3a)nO(CR3bR3c)n wherein n is 0 or an integer of 1 to 3, R3, R3a, R3b and R3c are each independently hydrogen atom, optionally substituted C1-6 straight chain or branched chain alkyl group, C2-6 straight chain or branched chain alkenyl group, aryloxycarbonyl group, arylaminocarbonyl group, arylalkylsulfonyl group, arylalkyl group, optionally substituted acyl group, aryl group or C3-8 ring optionally substituted by up to 4 hetero atoms, P2a, P2b, P3a and P3b are each independently hydrogen atom or optionally substituted straight chain, branched chain or cyclic C1-5 alkyl group, G is linking moiety, M is anchor moiety, J is bond, alkylene group, alkenylene group or alkynylene group, D is hydrogen atom, alkyl group, alkenyl group, alkynyl group or aryl group or may be bonded with G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is 0 or an integer of 1 to 3, wherein the anchor moiety in each formula is exemplified by thiazole group and oxazole group having, as a substituent, aryl group or heteroaryl group substituted by —NR′R″, —CONR′R″, —S(O)2NR′R″, —S(O)0-2R′, —NR′R″, —O(CR′R″)0-2CF3, —COR′, —CO2R′ and —OR′ wherein R′ and R″ are each independently hydrogen atom, C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group or optionally substituted aryl group, and the linking moiety is exemplified by covalent bond and C1-6 alkyl group.
Moreover, a compound represented by the formula
wherein M is carbocyclic group, heterocyclic group or CONR′R″ wherein R′ and R″ are each independently hydrogen atom, C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group or optionally substituted aryl group, Q is bond, oxygen atom, sulfur atom, CR3OH, CR3SH, CR3NR3aR3b, NR3, (CR3R3a)n, O(CR3R3b)n or (CR3R3a)nO(CR3bR3c)n wherein n is 0 or an integer of 1 to 3, R3, R3aR3b and R3c are each independently hydrogen atom, optionally substituted branched chain, cyclic or straight chain C1-6 alkyl group, C2-6 alkenyl group, acyl group, arylalkyl group, aryloxycarbonyl group, arylaminocarbonyl group, arylalkylsulfonyl group or aryl group, K is independently selected sublinking moiety, L is independently selected subanchor moiety, P4 is hydrogen atom, carboxy group, (CH2)1-4SP4′, cleavable prodrug moiety, COOP4′ or CONP4′P4″, R7 is hydrogen atom, carboxy group, aroyl group, aryl group, COOR7′, C(O)NR7′R7″, hydroxyl group, ether, thiol, (CH2)1-4SR7′, heterocyclic group or cleavable prodrug moiety, P4′, P4″, R7′ and R7″ are each independently hydrogen atom, C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group or optionally substituted aryl group, n is 0 or an integer of 1 to 4, D is hydrogen atom, alkyl group, alkoxy group, alkenyl group, amine, hydroxyl group, alkynyl group, aryl group or heteroaryl group, and t is 0 or 1, is described, wherein the sublinking moiety has a covalent bond and the subanchor moiety has an optionally substituted aryl group.
However, this publication does not disclose a compound having a structure as that of the compound of the present invention, not to mention a description suggestive thereof. In addition, the compound of this publication is useful as an angiotensin converting enzyme (ACE)-2 regulator, and the publication does not disclose its usefulness as a PTP1B inhibitor, not to mention a description suggestive thereof.